Higher frequency of cardiovascular autonomic neuropathy in youth with type 2 compared to type 1 diabetes: Role of cardiometabolic risk factors.

OBJECTIVE: Cardiovascular autonomic neuropathy (CAN) is an overlooked but common and serious diabetes complication. We examined CAN in youth with diabetes and associations with cardiovascular risk factors. RESEARCH DESIGN AND METHODS: This was a prospective cohort of youth aged <20 years with type 2 or type 1 diabetes (n = 66/1153, median age 15.4/16.5 years, duration 1.7/8.0 years), assessed between 2009 and 2020. CAN was defined as ≥2 abnormal heart rate variability measures across time, geometric, and frequency domains. Obesity was defined as BMI ≥ 95th percentile and severe obesity as ≥120% of 95th percentile. Multivariable generalized estimating equations (GEE) were used to examine putative risk factors for CAN, including diabetes type, obesity, and HbA1c . RESULTS: At most recent assessment, youth with type 2 versus type 1 diabetes had median: HbA1 c 7.1% (54 mmol/mol) versus 8.7% (72 mmol/mol) and BMI SDS (2.0 vs. 0.7); frequency of CAN (47% vs. 27%), peripheral nerve abnormality (47% vs. 25%), hypertension (29% vs. 12%), albuminuria (21% vs. 3%), and severe obesity (35% vs. 2%). In multivariable GEE, CAN was associated with type 2 diabetes: Odds Ratio 2.53, 95% CI 1.46, 4.38, p = 0.001, higher BMI SDS: 1.49, 95% CI 1.29, 1.73, p < 0.0001, and obesity: 2.09, 95% CI 1.57, 2.78, p < 0.0001. CONCLUSIONS: Youth with type 2 diabetes have a higher frequency of CAN, peripheral nerve abnormality, hypertension, albuminuria and severe obesity despite shorter diabetes duration and younger age. Our findings highlight the importance of targeting modifiable risk factors to prevent cardiovascular disease in youth with diabetes.

Thyroid nodules in children and adolescents: Investigation and management.

Clinically detectable thyroid nodules are less common in children than adults. However, they are associated with an increased risk of malignancy. Therefore, thorough evaluation of paediatric thyroid nodules is necessary, and an understanding of the features associated with a higher risk of malignancy is important to guide management and referral. Thyroid cancer in children differs significantly from that seen in adults in terms of genetics, presentation, response to treatment and prognosis. Children often present with more advanced disease, but the vast majority have excellent long-term prognosis. Evaluation and management of thyroid nodules and thyroid cancer require a multidisciplinary team approach and involvement of specialists with experience in this field. This review summarises investigative pathways for thyroid nodules in children and outlines current management strategies for paediatric thyroid nodules and cancer.

Sight-threatening retinopathy in nine adolescents with early onset type 1 diabetes.

In adults, there has been a decline in the incidence of diabetic retinopathy (DR) associated with improvements in diabetes management. Data on incident severe DR in adolescents are sparse. In our established diabetes complications assessment service, we recorded nine cases of sight-threatening retinopathy in youth aged 15-17.9 years from 2017 to 2021. Proliferative retinopathy and clinically significant macular oedema were identified. The subjects were diagnosed with type 1 diabetes before the age of 10 years and had a history of poor glycaemic control (HbA1c 86-130 mmol/mol, 10%-15%). Five cases of retinopathy developed rapidly within 2.5 years of a previously normal retinal examination on seven-field stereoscopic retinal photography. Three adolescents required laser photocoagulation therapy. Two adolescents were diagnosed with retinopathy following improvement in diabetes control after being lost to medical follow-up and their retinopathy improved with improved glycaemic control. Thus, we support repeated retinal screening in adolescents with diabetes duration >10 years with suboptimal glycaemic control, even when initial retinal examination is normal, as retinopathy can progress rapidly during adolescence.

Associations between circulating inflammatory markers, diabetes type and complications in youth.

BACKGROUND: Inflammation is implicated in the pathogenesis of diabetes and its complications in adults. Little is known about the relative contribution of inflammation in common types of diabetes in youth: type 1 diabetes (T1D), type 2 diabetes (T2D), and cystic fibrosis-related diabetes (CFRD). This study investigates inflammatory markers by diabetes type and complication status, and assesses indicators of inflammation and complications. METHODS: A cross-sectional study of 134 T1D, 32 T2D, 32 CFRD and 48 subjects without diabetes (including 11 with CF and normal glucose tolerance) was undertaken. Inflammation was assessed by sE-selectin by ELISA, hsCRP by turbidimetry, WCC and ESR. Nephropathy was defined by albuminuria, autonomic neuropathy by heart rate variability, and peripheral neuropathy by vibration and thermal threshold testing and retinopathy by seven-field stereoscopic fundus photography. Descriptive statistics, parametric and non-parametric ANOVA and regression analyses were performed, with significance at P < .05. RESULTS: Of 198 diabetic participants; 49% female, mean (SD) age, median diabetes duration and median HbA1c were 16 (2.5) and 6 (3-9) years, and 8.1 (6.9-9.3)%, respectively. All inflammatory markers were lower in T1D than in other diabetes groups (P < .05) but higher than in non-diabetic controls. T2D (n = 32) and CFRD (n = 32) subjects had comparable elevated levels of inflammation. Body mass index (BMI) was a strong independent explanatory variable of inflammation. In multivariate analysis, hsCRP and ESR were associated with complications in addition to HbA1c, BMI, and diastolic BP. CONCLUSIONS: Circulating inflammatory markers are elevated in adolescents with diabetes, being higher and comparable in T2D and CFRD than in T1D. Inflammation is independently associated with diabetes complications, consistent with inflammation driving vascular pathology in diabetes.

Endocrine and metabolic consequences due to restrictive carbohydrate diets in children with type 1 diabetes: An illustrative case series.

Low carbohydrate diets for the management of type 1 diabetes have been popularised by social media. The promotion of a low carbohydrate diet in lay media is in contrast to published pediatric diabetes guidelines that endorse a balanced diet from a variety of foods for optimal growth and development in children with type 1 diabetes. This can be a source of conflict in clinical practice. We describe a series of 6 cases where adoption of a low carbohydrate diet in children impacted growth and cardiovascular risk factors with potential long-term sequelae. These cases support current clinical guidelines for children with diabetes that promote a diet where total energy intake is derived from balanced macronutrient sources.

Heart rate variability in pubertal girls with type 1 diabetes: its relationship with glycaemic control, insulin resistance and hyperandrogenism.

OBJECTIVE: To examine the association between glycaemic control, insulin resistance and hyperandrogenism on cardiac autonomic function in peripubertal girls with type 1 diabetes. DESIGN: Prospective, clinic-based study of 125 girls with diabetes and 46 age-matched nondiabetic girls. MEASUREMENTS: Heart rate variability (HRV) parameters derived from a 10-min ECG recording using LabChart Pro were as follows: standard deviation of mean NN intervals (SDNN), where NN = adjacent QRS complexes; root mean squared difference of successive NN intervals (RMSSD) - estimates of overall HRV; and low-/high-frequency (LF:HF) ratio - an estimate of the sympathovagal balance. Androgens and sex hormone binding globulin (SHBG) were measured in girls with diabetes, and free androgen index (FAI) calculated. HRV and anthropometry were measured in nondiabetic controls. RESULTS: Adolescents with diabetes (median age 15·1 years [13·3-16·0], diabetes duration 7·0 years [4·6-10·0] and median HbA1c 8·4% [7·5-9·3]) had higher HR and lower HRV compared with controls. Using multivariate models in the diabetes group, higher HR was associated with higher HbA1c, total daily dose insulin/kg body weight and systolic BP standard deviation scores (SDS), whilst reduced HRV was associated with higher HbA1c (SDNN, RMSSD and LF:HF ratio), lower SHBG (SDNN and RMSSD) and higher weight SDS (LF:HF ratio). Higher FAI was associated with higher HR and reduced HRV measures in the univariate analyses only. CONCLUSIONS: In adolescent girls with diabetes, reduced HRV parameters are associated with worse glycaemic control, lower SHBG and higher weight SDS. SHBG should be considered in the cardiac risk models for this population.

Puberty as an accelerator for diabetes complications.

Much is written about how difficult it is to deal with diabetes during adolescence, and rightly so. Less is understood as to how puberty may be an accelerator of vascular complications. With the increase in childhood diabetes, complication risks need to be revisited in relation to puberty and the secular increase in adiposity. Recent data suggest greater risk for severe vascular complications in those with diabetes during puberty, compared with young people who develop diabetes after puberty. It is also widely recognized that higher hemoglobin A1c (HbA1c) results are often seen during the pubertal period. This article will review complication outcomes in relation to puberty and examine mechanisms by which puberty may modify risk above glycemic exposure, and possible gender disparities in the risk of complications in the adolescent period.

Autonomic neuropathy in young people with type 1 diabetes: a systematic review.

Autonomic neuropathy is an under-recognized complication of diabetes, although it affects multiple organ systems and has widespread clinical manifestations including orthostatic hypotension, exercise intolerance, gastroparesis, diarrhea, constipation, and urinary incontinence. The most severe consequences include hypoglycemia unawareness and cardiovascular dysfunction. Autonomic neuropathy is also implicated in sudden unexplained deaths in otherwise healthy young people--the 'dead in bed syndrome'. In adults, cardiovascular autonomic neuropathy is an independent predictor of mortality, predominantly due to cardiovascular disease, nephropathy, and hypoglycemia. While overt autonomic neuropathy is rare in childhood and adolescence, subclinical signs of autonomic dysfunction are common, and can be found soon after diabetes diagnosis. Risk factors for autonomic neuropathy in young people include diabetes duration, poor glycemic control, and presence of aldose reductase gene (AKR1B1) polymorphisms, specifically the Z-2/Z-2 genotype. Autonomic dysfunction is accelerated by puberty.

Highlights from the 37th Annual Meeting for ISPAD, Miami.

The 37th Annual Meeting for the International Society of Pediatric and Adolescent Diabetes was held in Miami Beach, Florida, USA. The meeting, titled 'Possibilities for Prevention and Diabetes and its Complications', attracted over 1000 delegates from 52 countries. Fifty-six oral abstracts were presented, along with 294 posters, representing the diversity of research and clinical innovations in the field of pediatric and adolescent diabetes around the world. Abstracts to the Oral and Poster Sessions can be found in a recent supplement of Pediatric Diabetes. Here are some highlights from the plenary sessions, symposia, and oral presentations.

Cardiac Autonomic Nerve Dysfunction Predicts Incident Retinopathy and Early Kidney Dysfunction in Adolescents With Type 1 Diabetes.

OBJECTIVE: Cardiac autonomic neuropathy (CAN) may contribute to vascular complications in diabetes. We hypothesized that adolescents with CAN are at greater risk of diabetic retinopathy and early kidney dysfunction. RESEARCH DESIGN AND METHODS: In this prospective longitudinal study of 725 adolescents with type 1 diabetes without retinopathy and albuminuria at baseline, early CAN was defined as one or more abnormalities in seven heart rate tests derived from a 10-min electrocardiogram. Retinopathy was defined as the presence of one or more microaneurysms, early kidney dysfunction as an albumin excretion rate (AER) >7.5 µg/min, and albuminuria as an AER >20 µg/min. Multivariable generalized estimating equations were used to examine the association between CAN and retinopathy or early kidney dysfunction. Cox proportional hazards regression analysis was used to assess cumulative risks of incident retinopathy and albuminuria. RESULTS: At baseline, the mean age of the sample was 13.6 ± 2.6 years, 52% were male, and mean diabetes duration was 6.1 ± 3.3 years. Over a median follow-up of 3.8 (interquartile range 2.2-7.5) years, the complication rate 27% for retinopathy, 16% for early kidney dysfunction, and 3% for albuminuria. The mean study HbA1c was 72.3 ± 16 mmol/mmol (8.6 ± 1.4%). CAN predicted incident retinopathy (odds ratio 2.0 [95% CI 1.4, 2.9]) and early kidney dysfunction (1.4 [1.0, 2.0]) after adjusting for HbA1c and diabetes duration. CAN also predicted retinopathy (hazard ratio 1.57 [95% CI 1.09, 2.26]) and albuminuria (2.30 [1.05, 5.04]) independently of HbA1c. CONCLUSIONS: CAN predicted incident retinopathy and kidney dysfunction in adolescents with type 1 diabetes, likely reflecting autonomic microvascular dysregulation contributing to complications. Therefore, screening and interventions to reduce CAN may influence the risk of complications.

Thirty-Year Time Trends in Diabetic Retinopathy and Macular Edema in Youth With Type 1 Diabetes.

OBJECTIVE: To examine trends in diabetic retinopathy (DR) and diabetic macular edema (DME) in adolescents with type 1 diabetes between 1990 and 2019. RESEARCH DESIGN AND METHODS: We analyzed 5,487 complication assessments for 2,404 adolescents (52.7% female, aged 12-20 years, diabetes duration >5 years), stratified by three decades (1990-1999, 2000-2009, 2010-2019). DR and DME were graded according to the modified Airlie House classification from seven-field stereoscopic fundal photography. RESULTS: Over three decades, the prevalence of DR was 40, 21, and 20% (P < 0.001) and DME 1.4, 0.5, and 0.9% (P = 0.13), respectively, for 1990-1999, 2000-2009, and 2010-2019. Continuous subcutaneous insulin infusion (CSII) use increased (0, 12, and 55%; P < 0.001); mean HbA1c was bimodal (8.7, 8.5, and 8.7%; P < 0.001), and the proportion of adolescents meeting target HbA1c <7% did not change significantly (8.3, 7.7, and 7.1%; P = 0.63). In multivariable generalized estimating equation analysis, DR was associated with 1-2 daily injections (odds ratio 1.88, 95% CI 1.42-2.48) and multiple injections in comparison with CSII (1.38, 1.09-1.74); older age (1.11, 1.07-1.15), higher HbA1c (1.19, 1.05-1.15), longer diabetes duration (1.15, 1.12-1.18), overweight/obesity (1.27, 1.08-1.49) and higher diastolic blood pressure SDS (1.11, 1.01-1.21). DME was associated with 1-2 daily injections (3.26, 1.72-6.19), longer diabetes duration (1.26, 1.12-1.41), higher diastolic blood pressure SDS (1.66, 1.22-2.27), higher HbA1c (1.28, 1.03-1.59), and elevated cholesterol (3.78, 1.84-7.76). CONCLUSIONS: One in five adolescents with type 1 diabetes had DR in the last decade. These findings support contemporary guidelines for lower glycemic targets, increasing CSII use, and targeting modifiable risk factors including blood pressure, cholesterol, and overweight/obesity.

Optimal Frequency of Retinopathy Screening in Adolescents With Type 1 Diabetes: Markov Modeling Approach Based on 30 Years of Data.

OBJECTIVE: Current guidelines recommend biennial diabetic retinopathy (DR) screening commencing at the age of 11 years and after 2-5 years' duration of type 1 diabetes. Growing evidence suggests less frequent screening may be feasible. RESEARCH DESIGN AND METHODS: Prospective data were collected from 2,063 youth with type 1 diabetes who were screened two or more times between 1990 and 2019. Baseline (mean ± SD) age was 13.3 ± 1.8 years, HbA1c was 8.6 ± 1.3% (70.1 ± 14.7 mmol/mol), diabetes duration was 5.6 ± 2.8 years, and follow-up time was 4.8 ± 2.8 years. DR was manually graded from 7-field retinal photographs using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Markov chain was used to calculate probabilities of DR change over time and hazard ratio (HR) of DR stage transition. RESULTS: The incidence of moderate nonproliferative DR (MNPDR) or worse was 8.6 per 1,000 patient-years. Probabilities of transition to this state after a 3-year interval were from no DR, 1.3%; from minimal DR, 5.1%; and from mild DR, 22.2%, respectively. HRs (95% CIs) for transition per 1% current HbA1c increase were 1.23 (1.16-1.31) from no DR to minimal NPDR, 1.12 (1.03-1.23) from minimal to mild NPDR, and 1.28 (1.13-1.46) from mild to MNPDR or worse. HbA1c alone explained 27% of the transitions between no retinopathy and MNPDR or worse. The addition of diabetes duration into the model increased this value to 31% (P = 0.03). Risk was also increased by female sex and higher attained age. CONCLUSIONS: These results support less frequent DR screening in youth with type 1 diabetes without DR and short duration. Although DR progression to advanced stages is generally slow, higher HbA1c greatly accelerates it.

Microvascular complications assessment in adolescents with 2- to 5-yr duration of type 1 diabetes from 1990 to 2006.

OBJECTIVE: Microvascular complications occur in adolescents with type 1 diabetes, although guidelines vary as to when screening should commence and prevalence data for those with ≤5-yr duration are limited. We therefore investigated trends in prevalence of early microvascular complications over 17 yr. RESEARCH DESIGN AND METHODS: 819 adolescents (54% female) aged 11-17 yr with 2- to 5-yr diabetes duration were assessed for complications at a tertiary pediatric diabetes clinic between 1990 and 2006. Early retinopathy was detected using seven-field fundal photography, albumin excretion rate (AER) by timed overnight urine collections and peripheral nerve function by thermal/vibration threshold at the foot. Results were analyzed by age, time period of assessment, and duration. RESULTS: Early retinopathy declined from 1990 to 2002 (16-7%, p < 0.01), then remained unchanged until 2006. Early elevation of AER (≥7.5 µg/min) and microalbuminuria (≥20 µg/min) did not change over time, whereas peripheral nerve abnormalities increased (14-28%, p < 0.01). Median hemoglobin A1c improved (8.7-8.2%, p < 0.01), in parallel with increased total daily insulin dose and injections per day (p < 0.01). Body mass index standard deviation score increased over time (0.55-0.79, p < 0.01). In multivariate logistic regression, early retinopathy was associated with earlier time period [odds ratio (OR) 0.68, confidence interval (CI) 0.55-0.85, p < 0.01] and older age (OR 1.19, CI 1.02-1.39, p = 0.03). AER ≥ 7.5 µg/min was associated with older age (1.19, 1.06-1.34, p < 0.01) and longer diabetes duration (OR 1.28, CI 1.02-1.62, p = 0.04) and height-adjusted peripheral nerve abnormalities with later time period (OR 1.26, CI 1.05-1.50, p = 0.01). CONCLUSIONS: Early complications are not uncommon in adolescents with 2- to 5-yr diabetes duration, despite more intensive management in recent years.

Insulin micro-secretion in Type 1 diabetes and related microRNA profiles.

The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10-20 years and > 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p < 0.0001 and in all (n = 253) participants without diabetes (CON). C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group [median lower quartile (LQ)-upper quartile (UQ)] 5.0 (2.6-28.7) versus 650.9 (401.2-732.4) pmol/L respectively, p < 0.0001 and lower in childhood versus adult-onset diabetes [median (LQ-UQ) 4.2 (2.6-12.2) pmol/L vs. 8.0 (2.3-80.5) pmol/L, p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend < 0.05). Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited.

Complications of childhood diabetes and the role of technology.

Technology for detecting vascular complications of childhood diabetes has already helped many children and youth by allowing for the early detection and intervention of impending or present problems as the result of the diabetes state. Prior to the advent of screening, young people developed clinical disease, in particular visual loss and renal impairment that often rapidly progressed to end-stage disease. With the advent of laser photocoagulation, which dramatically reduced visual loss from diabetic retinopathy, the importance of early detection and treatment of micro and macrovascular complications prior to clinical symptoms became apparent. Many technological advances are now being applied to the pediatric diabetes population, in either clinical care or the research setting. For example, retinal photography makes screening more accessible and more meaningful to adolescents with diabetes and can be used in large screening programs, for teleophthalmology, clinical trials and in geographically remote areas. Quantitative measures used to assess microvascular structure may be useful in monitoring interventions in the future. Quantitative sensory tests can monitor nerve dysfunction, but evaluations such as intraepidermal nerve fibre pathology and cornea confocal microscopy may be more sensitive to diagnose neuropathic complications in youth. B-mode ultrasonography can assess vascular function by measuring endothelium-dependent flow mediated dilatation and changes in the intima-media thickness of the carotid and aorta. It is the purpose of this manuscript to explore the role of present and future technological advances (Table 1) in young people with diabetes.

Insulin Pump Therapy Is Associated with Lower Rates of Retinopathy and Peripheral Nerve Abnormality.

OBJECTIVE: To compare rates of microvascular complications in adolescents with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI). RESEARCH DESIGN AND METHODS: Prospective cohort of 989 patients (aged 12-20 years; diabetes duration >5 years) treated with CSII or MDI for >12 months. Microvascular complications were assessed from 2000-14: early retinopathy (seven-field fundal photography), peripheral nerve function (thermal and vibration threshold testing), autonomic nerve abnormality (heart rate variability analysis of electrocardiogram recordings) and albuminuria (albumin creatinine ratio/timed overnight albumin excretion). Generalized estimating equations (GEE) were used to examine the relationship between treatment and complications rates, adjusting for socio-economic status (SES) and known risk factors including HbA1c and diabetes duration. RESULTS: Comparing CSII with MDI: HbA1C was 8.6% [70mmol/mol] vs. 8.7% [72 mmol/mol]) (p = 0.7), retinopathy 17% vs. 22% (p = 0.06); microalbuminuria 1% vs. 4% (p = 0.07), peripheral nerve abnormality 27% vs. 33% (p = 0.108) and autonomic nerve abnormality 24% vs. 28% (p = 0.401). In multivariable GEE, CSII use was associated with lower rates of retinopathy (OR 0.66, 95% CI 0.45-0.95, p = 0.029) and peripheral nerve abnormality (OR 0.63, 95% CI 0.42-0.95, p = 0.026), but not albuminuria (OR 0.46, 95% CI 0.10-2.17, p = 0.33). SES was not associated with any of the complication outcomes. CONCLUSIONS: In adolescents, CSII use is associated with lower rates of retinopathy and peripheral nerve abnormality, suggesting an apparent benefit of CSII over MDI independent of glycemic control or SES.

Association Between HbA1c Variability and Risk of Microvascular Complications in Adolescents With Type 1 Diabetes.

CONTEXT: There is a paucity of data regarding the association between glycosylated hemoglobin (HbA1c) variability and risk of microvascular complications in adolescents with type 1 diabetes (T1D). OBJECTIVE: To investigate the association between HbA1c variability and risk of microvascular complications in adolescents with T1D. DESIGN: Prospective cohort study from 1990 to 2014 (median follow-up, 8.1 y). SETTING: Tertiary pediatric hospital. PARTICIPANTS: A total of 1706 adolescents (aged 12-20 minimum diabetes duration 5 y) with median age of 15.9 years (interquartile range, 14.3-17.5) and diabetes duration of 8.1 years (6.3-10.8). MAIN OUTCOME MEASURES: Glycemic variability was computed as the SD of all HbA1c measurements (SD-HbA1c) after diagnosis. Retinopathy was detected using 7-field fundal photography, renal function assessed using albumin excretion rate, peripheral neuropathy detected using thermal and vibration threshold testing, and cardiac autonomic neuropathy (CAN) detected using time- and frequency-domain analyses of electrocardiogram recordings. Generalized estimating equations were used to examine the relationship between complications outcomes and HbA1c variability, after adjusting for known risk factors, including HbA1c, diabetes duration, blood pressure, and lipids. RESULTS: In multivariable analysis, SD-HbA1c was associated with early retinopathy (odds ratio [OR] 1.32; 95% confidence interval, 1.00-1.73), albuminuria (OR 1.81; 1.04-3.14), increased log10 albumin excretion rate (OR 1.10; 1.05-1.15) and CAN (OR 2.28; 1.23-4.21) but not peripheral neuropathy. CONCLUSIONS: Greater HbA1c variability predicts retinopathy, early nephropathy, and CAN, in addition to established risk factors, in adolescents with T1D. Minimizing long term fluctuations in glycemia may provide additional protection against the development of microvascular complications.

Cardiac autonomic dysfunction is associated with high-risk albumin-to-creatinine ratio in young adolescents with type 1 diabetes in AdDIT (adolescent type 1 diabetes cardio-renal interventional trial).

OBJECTIVE: This study examined the association between cardiac autonomic dysfunction and high albumin-to-creatinine ratio (ACR) in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Adolescents recruited as part of a multicenter screening study (n = 445, 49% female, aged 10-17 years, mean duration 6.9 years; mean HbA1c 8.4%, 68 mmol/mol) underwent a 10-min continuous electrocardiogram recording for heart rate variability analysis. Time-domain heart rate variability measures included baseline heart rate, SD of the R-R interval (SDNN), and root mean squared difference of successive R-R intervals (RMSSD). Spectral analysis included sympathetic (low-frequency) and parasympathetic (high-frequency) components. Standardized ACR were calculated from six early morning urine collections using an established algorithm, reflecting age, sex, and duration, and stratified into ACR tertiles, where the upper tertile reflects higher nephropathy risk. RESULTS: The upper-tertile ACR group had a faster heart rate (76 vs. 73 bpm; P < 0.01) and less heart rate variability (SDNN 68 vs. 76 ms, P = 0.02; RMSSD 63 vs. 71 ms, P = 0.04). HbA1c was 8.5% (69 mmol/mmol) in the upper tertile vs. 8.3% (67 mmol/mol) in the lower tertiles (P = 0.07). In multivariable analysis, upper-tertile ACR was associated with faster heart rate (ß = 2.5, 95% CI 0.2-4.8, P = 0.03) and lower RMSSD (ß = -9.5, 95% CI -18.2 to -0.8, P = 0.03), independent of age and HbA1c. CONCLUSIONS: Adolescents at potentially higher risk for nephropathy show an adverse cardiac autonomic profile, indicating sympathetic overdrive, compared with the lower-risk group. Longitudinal follow-up of this cohort will further characterize the relationship between autonomic and renal dysfunction and the effect of interventions in this population.

Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R).

CONTEXT: IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R). More than nine heterozygous mutations, including one compound heterozygous mutation, of the IGF1R gene have been reported in patients with varying degrees of intrauterine and postnatal growth retardation. OBJECTIVE: The objective of the study was the analysis of the IGF1R gene in a short-statured patient. PATIENT: The male patient, with a height of -5.91 sd score (aged 20.3 yr), had consistently elevated circulating serum concentrations of IGF-I. A diagnosis of antibody-negative insulin-requiring diabetes was made at age 14 yr. His deceased sister was also severely short statured (-3.75 sd score). RESULTS: The patient and his sister carried novel, compound heterozygous IGF1R missense mutations, E121K (exon 2) and E234K (exon 3), inherited from the mother and father, respectively. In vitro reconstitution studies demonstrated that neither the E121K nor E234K mutation affected IGF1R prepeptide expression, but levels of the proteolytically cleaved α- and ß-subunit were consistently low. As a consequence, each IGF1R variant exhibited significantly reduced IGF-I-induced signal transduction. Correlating to these studies, expression of functional IGF1R and the IGF-I-induced activation of the IGF1R pathway were markedly reduced in the primary dermal fibroblasts established from the patient. CONCLUSIONS: Only the second compound heterozygous IGF1R mutations to be identified, the p.E121K/E234K variant is the cause of intrauterine growth retardation and the most severe postnatal growth failure described to date in a patient with IGF1R defects. Whether the mutant IGF1R also contributes to the diabetic phenotype, however, remains to be determined.